Process for preparing lysine



in very low yields;

lysine.

Patented July 15, i952 1 UNITED. :srATE enooiiss FOR PiiEeARINc. I I SINEI Roger Gaudry, Quebec, Quebec; Canada, .assignoi to Ayerst, McKenna &-.Harrison,-;.Limited;

.Montreal, Quebec; Canada, a. corporation of Canada l I No Drawing. Application"1)eceinber Serial No. 789,711 I Claims. (01. zoo- 4654i This inventionrelates to the synthesis omganic compounds, especiallytoth'e synthesis of amino acids and more particularly, thesynthesis of .dl-lysine. I I

- Processes for the production of dll ysine" by prior syntheses involvethe disadvantages of be,-

ing difiicultlyproducible on a commercial scale,

involve complex reactions and result in poor yields. When produced by isolation from natural sources such aswprotein hydrolysates, the process of isolationis-long and diflicult and also results The process of this invention results inthe production of dl-lysine in a simple and easy manher and in muchhigher yield th eretofore accomplished since by myprocedure all the reactions may be carried out in aqueous solution and intermediate compounds are readily purified by crystallization from water. '11" My invention also includes the production of new and useful. compounds suitable for many uses and especially as intermediates for the production of amino acids otherthan dl-lysine.

: One object of the present invention isthe production of new and useful compounds.

Another object of the invention is the provisionof I an improved method for preparing certain amino acids; I I

A still further object of the inventionis to provide an improved method for obtaining dl- Other objects} will become apparent to those skilled; in the art from thedisclosure'appearing herein b'elowr I I I In accordance. with the invention, the productionof new compoundsand dl-lysine is carried out byg-using deltahydroxy-valeraldehyde asthe starting material. The preparation of-this compound is taught in. the art and can easily be prepared in good yield by reacting th'e'commerdrochloric acid. Y I Y I Reacting delta-hydroxy-valeraldehyde with. gaseous HCN at room temperature yields the compound alpha, epsilon-'dih'ydroxy:caproicni trile which is easily isolatedf. Q As an alternative procedure, when delta-hydroxy-valeraldehyde is reacted with an alkali metal acid sulfite such sodium or potassium acid sulfite'a'nd' followed by the addition of an alkali metal cyanide, preierablypotassium cyanideyat room temperature and just enough water to dissolve the cyanide, the compoundalpha, epsilon-dihydroxy-caproic nitrile is formed and in large part separates from the solution as a colorless oily liquid in an upper layer. Residual amounts of the nitrile may be extracted from cially available dihydropyran with aqueous'hy- .5 19 7af f the solution by means of ether. The reaction is illustrated in the followingmanner:

Hermit- H0 s) H -(QHQ QE or, alternatively, HO-(CHQr-CHO NaHSOs KCN ;oH- o i1 c II i ,(OH When-alpha, epsiloh-dihydro'xy caproic nitrile is" heated in water at a-temperature' of about C. to about (3., preferably 50=55 C.,-"with an excess 'of ammonium carbonate, the compound 5-delta hydroxy-butyl-hydantoin is formed. The reaction is carriedout for about one to two hours and finally the temperature is increased to the boiling point to remove the excess ammonium carbonate.

The hydantoin compound is obtained in the form of crystals. The reaction is illustrated as follows:

. The compound 5-delta-hydroxy-butyl-hydantoin may now be halogenated to form 5-deltahalogeno-butyl-hydantoin by reacting the hydroxy compound with a halogenating agent such as an excess of 48% hydrobromic acid, thionyl chloride or bromide, phosphorous trichloride or phosphorous pentachloride or in fact any wellknown halogenating agent. It is preferred, however, to select an agent which can easily be sep- I V arated from the desired product on the comple- "tio'n-of the reaction and for this reason, hydrobromic acid is the preferred agent; The reaction proceeds as shown: I I

+ halogenatingagent i Following the amination, the 'reactionmixture reaction v dantoin to -delta-aminobutyl-hydantoin,the 5famine or in the form of. the hydrochloride. The 7 hydrolysis is carried out with an alkaline earth metal hydroxide such as bariumor calcium hydroxide or in fact, any basic'm'aterial which can.

be eventually separated easily from. the desired compound. Preferably barium hydroxide is used since it can be easily removed on termination of the reaction by the addition of ammonium carinorganic or organic acid. It can be, made into a large number" of salts, for example, a hydrochloride, sulfate, oxalate, picrate, picrolonate,

the copper salt, the mercury salt, etc.

The following examples illustrate the invention but it is to be understood that they are ,given merely for illustrative purposes and are not to be considered limitative of the invention.

bonate, in the form of a barium carbonate precip- V itate. The final hydrolysis reaction resulting in the formation of dl-lys ine is illustrated as'fol- Alternatively, instead of proceeding through (4) from 5-delta-halogenobutyl-hydelta-halogenobutyl-hydantoin may be reacted with potassium phthalimide at a temperature of 'about 160 C. for about one to about one and a half hours to form 5-delta-phthalimido-butylhydantoin. This compound may be i solated and recrystallized from 30% aqueous alcohol. On acid-hydrolysis preferably using dilute'HCl, the

phthalimido compound is convertedv to 5-deltaaminobutyl-hydantoin. These reactions are illustrated in-the following steps: (4a) I, -00 C0NH Har m- NH-PCO c0 OO-NH .Hydroly sis I this feature,

. co NH may be used as a starting material in preparing fdroxy+caproic 'acidby either acid or alkaline hydrolysis. With acid hydrolysis, the hydantoin compounds is boiled under reflux in an excess of 60% sulfuric acid followed by the removal of the mineral acid with barium hydroxide. The amino acid may'also be prepared by alkaline hydrolysis using an alkaline earth metal compound preferably barium hydroxide underrefiux conditions; or better under pressure, at 150-160 C., for a quarter to a half hour. Y

This new amino acid has been found to possessinteresting physiological action and is usefu1 eithenaS- he free base or as a salt of an running water.

As will'be apparent to thoseskilled in the art variations in conditions, in the quantities used and in the particular reactants employed will be obvious.

S-deZta-hydroxybutyl hydantoin Dihydropyran g., 1.19 mole) was hydrolyzed into. delta@hydroxy-valeraldehyde with 0.02 Nfihydrochloric acid. Aiter carefully neutralizing the solution with sodium hydroxide, dry sodium acid sulfite g., 1.20 mole) was, added with good mechanical stirring to the aqueous solution of they aldehyde kept at room'temper- 'ature' by'dipping the flask'into a bath of cold When all the sodium bisulfite had dissolved, a solution'of potassium cyanide (78 g., 1.2 mole) in water (100 ml.) was slowly added and stirring was continued at room temperature for two hours. The mixture was'poured into a separatory funnel, the upper-layer was separated and the aqueous layerwas extracted four times with .large volumes (4x250-ml.) of ether. The ether was evaporated on the waterbath, and the residue was added to the main portion from the upper layer. This liquid, which is nearly pure, colorless alpha-epsilondihydroxycaproic. nitrile, wasadded to'a solution of ammonium carbonate (2% g., 2.4 moles) in water (400 ml.) and the mixture was stirred for one hour while being kept at 5055 C. in a water bath. The temperature of the bath was then raised slowly to boiling, a little Norit added, the solution was filtered into a large evaporating dish and evaporated todryness on. a water-bath. The residue was recrystallizedfrom water; melting point: 152 to 155 C. Calc.'for CvHmOaNz: N, 16.27%. Found (Kjeldahl): N, 16.17%. a

' dl-AZpha-amino-epsilon-hydroa:ycaproic'acid 5-delta#hydroxybutylhydantoin (51.5 g., 0 .30 mole), barium hydroxide (15,-1.5 'g. of the octahydrate, 0.48 mole) and boiling water (750 were mixed together and the solution was'heat ed in an autoclave at 'C. for half an hour; The solution was cooled, filtered from the barium carbonate, treated with powdered ammonium carbonate (30 'g.), again filtered from the barium carbonate, and evaporated to dryness under reduced pressure. The residue was slurried with methanol and suction filtered to give pure dl-alpha amino epsilon hydroxycaproic acid. It is readily recrystallized from, water. The melting point varies between 245-2485;.(3. and 260+262 C. withevolution ofgas, according to the rate of heating... C'alc. for, CeHnOsNi N, 9.52%. Found (KjeldahDz N,, 935%. .The picrate melts at 127l30 0.. Calculated for C12H16O10N52 N, 14.89%. Found: N, 14.56%. 5-delta-bromobutylhydantoi n, v 5 delta hydroxybutylhydantoin (34.4 g5, 0.2 mole) was treated-with 48% hydrobromicacid (400 ml), and the solution was kept at 90 0.101 two :hours, in a water-bath. It was then evaporated to dryness in vacuo, the residue was dissolved in boiling water (300ml) boiled'undei' reflux for five minutes with a little Norit, filtered, and allowed to cool. The precipitate was filtered and the solution was evaporated to dryness in vacuo.

The residue was again treated with 48% hydrobromic acid (100 ml.) for two hours at 90 C., the acid was evaporated in vacuo, and the residue decolorized with Norit and crystallized from-hot water (30 ml.). After two crystallizations, the melting point was l29-131 C. C'alculated for C7H11O2N2BI: N, 11.97%. Found (Kjeldahl) N, 11.91%.

5 -delta-chlorobutylhydantoin 5-delta-hydroxybutylhydantoin (17.2 g., 0.1 mole) and thionyl chloride (7.6 g;, 0.1 mole) was rapidly mixed in a beaker with a glass rod, and allowed to stand for one hour at room temperature, under a hood. The mixture was then dissolved in hot water (100 ml.) and cooled. The precipitate was filtered and recrystallized from a little hot water. Melting point: 126-128" C. Calculated for C7H11O2N2C1: N, 14.70%. Found (Kjeldahl) N, 14.66%.

5-delta-phthalimid-obutylhydantoin After cooling, the mixture was filtered, and the solution treated with an excess of 'ammonium' of picric acid (23 g.) in boiling water (1200 ml.).

5 delta -bromobutylhydantoin (23.5 g., 0.1

mole) and potassium phthalimide (18.5 g., 0.1 mole) were intimately mixed in a mortar, the mixture was transferred to a conical flask and heated at 150 C. for one and a half hour in an oil bath. After cooling, the mass was washed in a mortar by decantation with three portions of water (100 ml.) and recrystallized from a mixture of water (225 ml.) and alcohol (150 ml). A high yield may be obtained by working up the mother liquor. After three crystallizations, the melting point was 212-215 C., with sinteringat about 170 C. Calculated for C15H1504N32 N, 13.95%. Found (Kjeldahl): N, 13.93%.

5-delta-aminobutylhydantoin 5 delta bromobutylhydantoin (7.83 g., mole) and concentrated ammonia (160 ml.) were placed in a 200 ml. pressure bottle, and the solution was heated at 60 C. for four days. The solution was evaporated to dryness in vacuo. The residue was dissolved in water (100 ml.), the solution was boiled for a few minutes with freshly precipitated silver oxide (4 g.) filtered, acidified with a slight excess of hydrochloric acid, and evaporated to dryness in vacuo. 5-deltaaminobutylhydantoin hydrochloride slowly solidified on standing. It is very soluble in Water and alcohol, and precipitates as an oil by adding ether 'to the alcoholic solution. It was not obtained in a pure state, but only as pale brownish powder which melted at 163-170 C. Calculated for C7H14O2N3Cl; N, 20.24%. Found (Kjeldahl) N, 19.25%. The picrate was obtained by treating the aqueous solution of the hydrochloride with one equivalent of picric acid and was recrystallized from very little water. Melting point, 180-183 C. It analyses for the monohydrate. Calculated for C13H1609N6H20Z N, 20.09%. Found: N, 20.01%.

(ll-Lysine 5-delta-bromobutylhydantoin (23.5 g., 0.1 mole) was aminated in presence of a large excess of concentrated ammonia (500 ml.) by heating for four days at 60 C. in pressure bottles. The solution was evaporated to dryness under reduced pressure. The residue was dissolved in a solution of barium hydroxide (78 g., 0.25 mole of the octahydrate) in hot water (500 ml.), and heated in an autoclave at 160 C. for one half hour.

The solution Was allowed to cool, and placed in the ice-box for 48 hours. Lysine dipicrate crystallized'out. A sample, which was recrystallized from a little hot water, melted at 188 C.,undepressed when mixed with an authentic sample. Pure dl-lysine dihydrochloride was readily obtained from the dipicrate, by treating the dipicrate with an excess of aqueous hydrochloric acid, filtering and extracting the last traces of picric acid with ether, decolorizing with Norit and evaporating to dryness in vacuo. The prodnot obtained was the dihydrate which melted at 186-189 C. after grinding with alcohol. Calc. for CeH1602N2C12. 21-120: N, 10.98%. (Kjeldahl): N, 10.91%.

The free base, i. e., dl-lysine may be obtained by treating the 'dihydrochloride with the calculated amount of silver oxide, as known to the art. As is also known to the art, the monohydrochloride of dl-lysine may also be obtained from the dihydrochloride.

I claim:

1. The new compound alpha-epsilon-dihydroxy caproic nitrile.

2. The process of preparing alpha, epsilondihydroxy-caproic nitrile comprising reacting delta-hydroxy-valeraldehyde with an alkali metal acid sulfite and an alkali metal cyanide in aqueous solution, said reaction being carried out at room temperature, and then separating the oily liquid product from the reaction mixture as the desired alpha, epsilon-dihydroxy-caproic nitrile.

3. The process of preparing alpha, epsilondihydroxy-caproic nitrile comprising adding an alkali metal acid sulfite to delta-hydroxyvaleraldehyde, adding to said mixture an aqueous solution of alkali metal cyanide and reacting the mixture at room temperature until an oily layer separates from the aqueous reaction mixture, and then isolating said oily reaction product as the desired alpha, epsilon-dihydroxy-caproic nitrile.

4. The process comprising, reacting the compound alpha, epsilon-dihydroxy-caproic nitrile by commingling said compound with ammonium droxy caproic nitrile reactant is formed by reacting delta-hydroxyvaleraldehyde with an alkali metal acid sulfite and an alkali metal cyanide in aqueous solution at room temperature.

ROGER GAUDRY.

vol. 67, De-

Found a 

1. THE NEW COMPOUND ALPHA-EPSILON-DIHYDROXY-CAPROIC NITRILE.
 4. THE PROCESS COMPRISING, REACTING THE COMPOUND ALPHA, EPSILON-DIHYDROCY-CAPROIC NITRILE BY COMMINGLING SAID COMPOUND WITH AMMONIUM CARBONATE IN AQUEOUS SOLUTION, SEPARATING OUT A HYDANTOIN REACTION PRODUCT, REACTING THE LATTER WITH A HALOGENATING AGENT TO FORM A HALOGENATED-ALKYLHYDANTOIN, TREATING THE LATTER WITH AN ALKALI METAL PHTHALIMIDE AT ELEVATED TEMPERATURES, ISOLATING THE 5-DELA-PHTHALIMIDO-BUTYL HYDANTOIN FORMED, HYDROLYZING THE PHTHALIMIDO REACTION PRODUCT TO FORM 5-DELTA-AMINOBUTYL-HYDANTOIN AND FINALLY FURTHER HYDROLYZING THE LASTNAMED COMPOUND TO FORM DI-LYSINE. 